Synchrotron radiation (SR) is an extremely bright and tunable x-ray source that enables forefront research in Structural molecular biology (SMB). A "Synchrotron Structural Biology Resource" is supported at the Stanford Synchrotron Radiation Lightsource (SSRL) by the NIH and DOE to develop new technologies in macromolecular crystallography, x-ray absorption spectroscopy and small angle x-ray scattering/diffraction, to train/support users, and to disseminate these capabilities to the biomedical research community. This proposal is for the continued funding, operation and future development of this Resource. New initiatives will capitalize on the increasing SR performance of SSRL's 3'" generation storage ring SPEARS. Proposed also is the development of selected SMB applications of the world's first x-ray free-electron laser (LCLS), just beginning operation at SLAC. A principal aim is to optimize experimental facilities and instrumentation, detectors, software and compute performance on the 9-i- SMB dedicated beam lines at SSRL (with another two in construction) to take full advantage of the high brightness provided by SPEAR3 at 500 mA current. This will enable the Resource to advance the scientific forefront with new initiatives built upon state-of-the-art instrumentation and methodologies, innovative software and automated/high-throughput systems for: studying high resolution structures/function of large, complex biomolecules and molecular machines;imaging the spatial distribution and chemical nature of elements in non-crystalline biological materials;investigating fundamental questions in biophysics such as protein and RNA folding;and developing/improving methods for studying very fast time-resolved structural changes in chemical and biological systems with ultrafast or fast scattering and absorption techniques. These scientific advancements will be facilitated by parallel developments in software to provide expanded capabilities for instrument and detector control, remote data collection and real-time data analysis. Driving biomedical projects and collaborative research programs involving a large number of outside scientists will drive and support core technological developments, the pace of translational research will be accelerated through collaborations with NCRR CTSA Centers, and a highly active program in training and dissemination will bring them to a wide user community. PUBLIC HEALTH RELEVANCE: Relevance is to a number of important biological problems including the structure of enzymes, metalloproteins, membrane-bound proteins and immunoglobulins;the active site structure of metalloproteins involved in metabolism and photosynthesis;and how these structures change in different states or evolve in time as reactions or events like protein folding or conformational changes occur. Such information is more broadly important to the health-related areas of drug design, cancer research, and virology.